The global introduction of 14 new antiepileptic drugs (AEDs) over the past 20 years as adjunctive treatment in refractory epilepsy has triggered an increased interest in optimising combination therapy. With a widening range of available mechanisms of AED action, much activity has been focused on the defining and refining “rational polytherapy” with AEDs that have differing pharmacological properties. This paper reviews the available animal and human data exploring this issue. The experimental and clinical evidence in support of “rational polytherapy” is sparse, with only the combination of sodium valproate with lamotrigine demonstrating synergism. Robust evidence to guide clinicians on how and when to combine AEDs is lacking and current practice recommendations are largely empirical. Practical guidance for the clinician is summarised and discussed in this review. In particular, care should be taken to avoid excessive drug load, which can be associated with decreased tolerability and, therefore, reduced likelihood of seizure freedom. A palliative strategy should be defined early for the more than 30% of patients with refractory epilepsy. Nevertheless, the availability of an increasing number of pharmacologically distinct AEDs has produced a modest improvement in prognosis with combination therapy, which will encourage the clinician to persevere with continued pharmacological manipulation when other therapeutic options have been tried or are not appropriate.
